Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for a s long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells can undergo rapid proliferation and turnover with a 5 day period. (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267: 10931-10934 (1987), and Folkman, J. and Klagsbrun, M., Science, 235: 442-447 (1987)).
Although angiogenesis is a highly regulated process under normal conditions, many disease (characterized s "angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman J., Cancer Research46 467-473 (1986). Folkman, J., Journal of the National Cancer Institute, 82: 4-6 (1989)0. It has been shown for example that tumors which enlarge to greater than 2 mm, must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324: 1-8 (1991)).
Because of this pivotal role played by neovacularization in tumor formation and metastasis and in such other disease conditions as arthritis, inflammation, maccular degeneration of age, and diabetic retinopathy, agents which inhibit angiogenesis have been the subject of active current research for their clinical potential.
D. Ingber, et al., in Nature, 348: 555-557 report that fumagillin, a natural product of fungal origin, and its synthetic analog, O-(chloroacetylcarbamoyl)fumagillol, also known as AGM-1470 or TNP-470, act as potent inhibitors of angiogenesis, with TNP-470 being 50-fold more potent than its natural precursor.
Ny Sin et al., Proc. Natl. Acad. Sci. USA94: 6099-6103 (1997) and Eric C. Griffith, et al., Chemistry and Biology, 4(6): 461-471 (1997) report that both AGM-1470 and ovalicin, a sequiterpene isolated from the fungus Pseudorotium ocalis bind to a common bifunctional protein, type 2 methionine aminopeptidase, MetAP2, and conclude that MetAP2 plays a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs.
J. Abe, et al., Cancer Research, 54: 3407-3412 (1994) report that fumagillin, and its derivative TNP-470, are effective in inhibiting neovacularization by arresting the endothelial cell cycle in the late G.sub.1 phase.
The literature has thus established a casual line between inhibition of MetAP2 and the resultant inhibition of endothelial cell proliferation and neovacularization. There is a need for discovery of new agents which inhibit MetAP2 for their potential as new drugs in combating angiogenesis or neovacularization and disease conditions such as arthritis, inflammation, maccular degeneration of the eye, diabetic retinopathy, and tumor growth which depend upon neovasculaturization for their development. Compounds of the current invention are structurally novel, reversible inhibitors of MetAP2 which may display improved pharmaceutical properties and diminished side effects relative to the currently known irreversible inhibitors such as fumagillin and TNP470.